title: A mild neurofibromatosis type 1 phenotype produced by the combination of the benign nature of a leaky NF1-splice mutation and the presence of a complex mosaicism.
abstract: Here we analyze the genetic and molecular basis responsible for a very benign phenotype observed in an NF1 patient. Quantification of cells carrying the NF1 mutation in different samples derived from the three embryonic layers revealed mosaicism. Furthermore, the construction of a minigene with patient's mutation (c.3198 - 314G>A) confirmed its benign nature due to the leakiness of the splicing mechanism that generated a proportion of correctly spliced transcripts. Hence, we concluded that the mild phenotype observed in this patient is the result of the presence of mosaicism together with the benign nature of a leaky NF1-splice mutation. Finally, with the aim of developing a personalized therapeutic approach for this patient, we demonstrated correction of the splicing defect by using specific antisense morpholino oligomers. Our results provide an example of the molecular complexity behind disease phenotypes and highlight the importance of using comprehensive genetic approaches to better assess phenotype-genotype correlations.
authors.affiliation: Hereditary Cancer Program, Genetic Diagnosis Unit, Institut Català d'Oncologia, Badalona, Barcelona, Spain.
authors.forename: Juana
authors.initials: J
authors.lastname: Fernández-Rodríguez
authors.forename: Joan
authors.initials: J
authors.lastname: Castellsagué
authors.forename: Llúcia
authors.initials: L
authors.lastname: Benito
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Benavente
authors.forename: Gabriel
authors.initials: G
authors.lastname: Capellá
authors.forename: Ignacio
authors.initials: I
authors.lastname: Blanco
authors.forename: Eduard
authors.initials: E
authors.lastname: Serra
authors.forename: Conxi
authors.initials: C
authors.lastname: Lázaro
mesh_terms: D000328:Adult; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D009030:Mosaicism; D009154:Mutation / Q000235:genetics; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000473:pathology*; D025542:Neurofibromin 1 / Q000235:genetics*; D020320:Oligoribonucleotides, Antisense; D010641:Phenotype; D057285:Precision Medicine; D020033:Protein Isoforms / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics
chemical_list: D025542:Neurofibromin 1; D020320:Oligoribonucleotides, Antisense; D020033:Protein Isoforms